An update on the formation in tobacco, toxicity and carcinogenicity of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein and CO2, all of which occur in high concentrations in cigarette smoke, are discussed.

Safety Assessment of Palm-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 8 palm tree (Euterpe edulis (juçara) and Euterpe oleracea (açaí))-derived ingredients as used in cosmetic products; these ingredients are reported to function mostly as skin conditioning agents. The Panel reviewed relevant data relating to the safety of these ingredients in cosmetic formulations. Industry should continue to use good manufacturing practices to limit impurities. The Panel concluded that palm tree (açaí and juçara)-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Safety Assessment of Polysilicone-11 as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Polysilicone-11 as used in cosmetic formulations. This ingredient is reported to function as a film former. The Panel considered the available data and concluded that Polysilicone-11 is safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Safety Assessment of Capryloyl Salicylic Acid as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of Capryloyl Salicylic Acid in cosmetic products; this ingredient is reported to function as a skin conditioning agent. The Panel reviewed relevant data relating to the safety of this ingredient in cosmetic formulations, and concluded that the available data are insufficient to make a determination that Capryloyl Salicylic Acid is safe under the intended conditions of use in cosmetic formulations.

Safety Assessment of Soy-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 28 soy-derived ingredients as used in cosmetic products. These ingredients are reported to primarily function as antioxidants, skin protectants, skin-conditioning agents, and hair-conditioning agents. The Panel considered the available data relating to the safety of these ingredients in cosmetic formulations, and concluded that 24 of the 28 soy-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment. The Panel also concluded that the available data are insufficient to make a determination that Glycine Max (Soybean) Callus Culture, Glycine Max (Soybean) Callus Culture Extract, Glycine Max (Soybean) Callus Extract, and Glycine Max (Soybean) Phytoplacenta Conditioned Media are safe under the intended conditions of use in cosmetic formulations.

Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis.

Humans are exposed to furan, a toxicant and possible human carcinogen, through multiple sources including diet and tobacco smoke. The urinary metabolites of furan are derived from the reaction of its toxic metabolite with protein nucleophiles and are biomarkers of exposure and potential harm. An established isotopic dilution liquid-chromatography mass spectrometry method was used to measure these biomarkers in urine from users of e-cigarettes, cannabis, and/or combustible tobacco with/without reduced nicotine levels. Amounts of furan mercapturic acid metabolites were higher in these individuals relative to nonsmokers, indicating that they may be at risk for potential furan-derived toxicities.

Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Concentrations of Per- and Polyfluoroalkyl Substances in Paired Maternal Plasma and Human Milk in the New Hampshire Birth Cohort.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent endocrine-disrupting chemicals associated with long-term health outcomes. PFAS are transferred from maternal blood to human milk, an important exposure source for infants, and understanding of this transfer is evolving. We characterized concentrations of 10 PFAS in human milk (n = 426) and compared milk-to-plasma concentrations of 9 PFAS among a subset of women with paired samples (n = 294) from the New Hampshire Birth Cohort Study using liquid chromatography-isotope dilution tandem mass spectrometry. We examined the relationship between perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in plasma versus milk and fit linear regression models to assess relationships between milk PFOA and PFOS and participant characteristics. The median plasma PFOA concentration was 0.94 ng/mL (interquartile range, IQR, 0.59-1.34) and that of PFOS was 2.60 ng/mL (IQR 1.80-3.90); the median milk PFOA concentration was 0.017 ng/mL (IQR 0.012-0.027) and that of PFOS was 0.024 ng/mL (IQR 0.016-0.036). PFOA and PFOS plasma and milk concentrations showed correlations of ρ = 0.83 and 0.77, respectively (p < 0.001). Parity, previous lactation, week of milk collection, and body mass index were inversely associated with milk PFAS. We estimate that even among our general population cohort, some infants (∼6.5%) are exposed to amounts of PFAS via milk that may have long-term health impacts.

Isopropyl Lanolate.

The Expert Panel for Cosmetic Ingredient Safety reviewed updated information that has become available since their original assessment from 1980, along with updated information regarding product types, and frequency and concentrations of use, and reaffirmed their original conclusion that Isopropyl Lanolate is safe as a cosmetic ingredient in the practices of use and concentration as described in this report.

Quaternium-18 and Quaternium-18 Bentonite.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982, along with updated information regarding product types and concentrations of use, and confirmed that Quaternium-18 and Quaternium-18 Bentonite are safe as cosmetic ingredients in the practices of use and concentration as described in this report.

Sulfites.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1998, along with updated information regarding product types and concentrations of use, and confirmed that Sodium Sulfite, Potassium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are safe as cosmetic ingredients in the practices of use and concentration as described in this report.

Safety Assessment of Cocos nucifera (Coconut)-Derived Ingredients as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 11 Cocos nucifera (coconut)-derived ingredients, most of which are reported to function as skin-conditioning agents in cosmetic products. The Panel reviewed the available data to determine the safety of these ingredients. The Panel concluded that 10 ingredients, derived from coconut flower, fruit, and liquid endosperm, are safe in cosmetics in the present practices of use and concentration described in this safety assessment, and that the available data are insufficient to make a determination of safety for Cocos Nucifera (Coconut) Shell Powder under the intended conditions of use in cosmetic formulations.

Methacrylate Ester Monomers.

The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 2005, along with updated information regarding product types and concentrations of use, and confirmed that these 22 methacrylate ester monomers are safe as used in nail enhancement products in the practices of use and concentration as described in this report, when skin contact is avoided.

Acrolein Increases the Pulmonary Tumorigenic Activity of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Tobacco smoke is a complex mixture of more than 7000 chemicals, of which many are toxic and/or carcinogenic. Many hazard assessments of tobacco have focused on individual chemical exposures without consideration of how the chemicals may interact with one another. Two chemicals, the human carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) and a possible human carcinogen, acrolein, were hypothesized to interact with one another, possibly owing to the additive effects of DNA adduct formation or influence on the repair of mutagenic DNA adducts. To test our hypothesis that coexposure to NNK and acrolein is more carcinogenic than either chemical alone, A/J mice were exposed to NNK (i.p., 0, 2.5, or 7.5 µmol in saline) in the presence or absence of inhaled acrolein (15 ppmV). While the single 3 h exposure to acrolein alone did not induce lung adenomas, it significantly enhanced NNK's lung carcinogenicity. In addition, mice receiving both NNK and acrolein had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that acrolein may also increase the severity of NNK-induced lung adenomas. To test the hypothesis that the interaction was due to effects on DNA adduct formation and repair, NNK- and acrolein pulmonary DNA adduct levels were assessed. There was no consistent effect of the coexposure on NNK-derived DNA adducts, and acrolein DNA adducts were not elevated above endogenous levels. This study supports the hypothesis that tobacco smoke chemicals combine to contribute to the carcinogenic potency of tobacco smoke, and the mechanism of interaction cannot be explained by alterations of DNA adduct levels.

Effects of GSTT1 Genotype on the Detoxification of 1,3-Butadiene Derived Diepoxide and Formation of Promutagenic DNA-DNA Cross-Links in Human Hapmap Cell Lines.

Smoking is a leading cause of lung cancer, accounting for 81% of lung cancer cases. Tobacco smoke contains over 5000 compounds, of which more than 70 have been classified as human carcinogens. Of the many tobacco smoke constituents, 1,3-butadiene (BD) has a high cancer risk index due to its tumorigenic potency and its abundance in cigarette smoke. The carcinogenicity of BD has been attributed to the formation of several epoxide metabolites, of which 1,2,3,4-diepoxybutane (DEB) is the most toxic and mutagenic. DEB is formed by two oxidation reactions carried out by cytochrome P450 monooxygenases, mainly CYP2E1. Glutathione-S-transferase theta 1 (GSTT1) facilitates the conjugation of DEB to glutathione as the first step of its detoxification and subsequent elimination via the mercapturic acid pathway. Human biomonitoring studies have revealed a strong association between GSTT1 copy number and urinary concentrations of BD-mercapturic acids, suggesting that it plays an important role in the metabolism of BD. To determine the extent that GSTT1 genotype affects the susceptibility of individuals to the toxic and genotoxic properties of DEB, GSTT1 negative and GSTT1 positive HapMap lymphoblastoid cell lines were treated with DEB, and the extent of apoptosis and micronuclei (MN) formation was assessed. These toxicological end points were compared to the formation of DEB-GSH conjugates and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) DNA-DNA cross-links. GSTT1 negative cell lines were more sensitive to DEB-induced apoptosis as compared to GSTT1 positive cell lines. Consistent with the protective effect of GSH conjugation against DEB-derived apoptosis, GSTT1 positive cell lines formed significantly more DEB-GSH conjugate than GSTT1 negative cell lines. However, GSTT1 genotype did not affect formation of MN or bis-N7G-BD cross-links. These results indicate that GSTT1 genotype significantly influences BD metabolism and acute toxicity.

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung.

Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNK-induced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 µmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNK-derived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.

Amended Safety Assessment of Methylchloroisothiazolinone and Methylisothiazolinone as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of the mixture Methylchloroisothiazolinone (MCI)/Methylisothiazolinone (MI), which functions as a preservative in cosmetic products. The Panel reviewed relevant animal and human data provided in this safety assessment, and data from the previously published safety assessment of this mixture, and concluded that MCI/MI is safe in cosmetics when formulated to be nonsensitizing, based on the results of a quantitative risk assessment or similar methodology; however, at no point should concentrations exceed 7.5 ppm in leave-on products or 15 ppm in rinse-off products.

Amended Safety Assessment of Methylisothiazolinone as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of Methylisothiazolinone, which functions as a preservative in cosmetics. The Panel reviewed relevant animal and human data provided in this safety assessment, and data from the previously published safety assessments of Methylisothiazolinone, and concluded that Methylisothiazolinone is safe for use in rinse-off cosmetic products at concentrations up to 100 ppm (ie, 0.01%) and safe in leave-on cosmetic products when they are formulated to be nonsensitizing, which may be determined based on a quantitative risk assessment or similar methodology.

Prenatal stress enhances NNK-induced lung tumors in A/J mice.

Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.

Interindividual Differences in DNA Adduct Formation and Detoxification of 1,3-Butadiene-Derived Epoxide in Human HapMap Cell Lines.

Smoking-induced lung cancer is a major cause of cancer mortality in the US and worldwide. While 11-24% of smokers will develop lung cancer, risk varies among individuals and ethnic/racial groups. Specifically, African American and Native Hawaiian cigarette smokers are more likely to get lung cancer as compared to Caucasians, Japanese Americans, and Latinos. It is important to identify smokers who are at the greatest risk of developing lung cancer as they should be candidates for smoking cessation and chemopreventive intervention programs. Among 60+ tobacco smoke carcinogens, 1,3-butadiene (BD) is one of the most potent and abundant (20-75 µg per cigarette in mainstream smoke and 205-361 µg per cigarette in side stream smoke). BD is metabolically activated to 3,4-epoxy-1-butene (EB), which can be detoxified by glutathione S-transferase theta 1 (GSTT1)-mediated conjugation with glutathione, or can react with DNA to form 7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) adducts. In the present study, we employed EBV-transformed human lymphoblastoid cell lines (HapMap cells) with known GSTT1 genotypes to examine the influence of the GSTT1 gene on interindividual variability in butadiene metabolism, DNA adduct formation/repair, and biological outcomes (apoptosis). We found that GSTT1- HapMap cells treated with EB in culture produced lower levels of glutathione conjugates and were more susceptible to apoptosis but had similar numbers of EB-GII adducts as GSTT1+ cells. Our results suggest that GSTT1 can influence an individual's susceptibility to butadiene-derived epoxides.